title: The oligomerization of a family of four genetically clustered human gastrointestinal mucins.
abstract: Mucins are synthesized and secreted by many epithelia. They are complex glycoproteins that offer cytoprotection. In their functional configuration, mucins form oligomers by a biosynthetic process that is poorly understood. A family of four human gastrointestinal mucin genes (MUC2, MUC5AC, MUC5B, and MUC6) is clustered to chromosome 11p15.5. To study oligomerization of these related mucins, we performed metabolic labeling experiments with [35S]amino acids in LS174T cells, and isolated mucin precursors by specific immunoprecipitations that were analyzed on SDS-PAGE. Each of the precursors of MUC2, MUC5AC, MUC5B, and MUC6 formed a single species of disulfide-linked homo-oligomer within 1 h after pulse labeling. Based on apparent molecular masses, these oligomeric precursors were most likely dimers. Inhibition of vesicular RER-to-Golgi transport, with brefeldin A and CCCP, did not affect the dimerization of MUC2 precursors, localizing dimerization to the RER. O-Glycosylation of MUC2 followed dimerization. Inhibition of N-glycosylation by tunicamycin retarded, but did not inhibit, dimerization, indicating that N-glycans play a role in efficient dimerization of MUC2 precursors. Based on sequence homology, the ability of MUC2, MUC5AC, MUC5B and MUC6 to dimerize most likely resides in their C-terminal domains. Thus, the RER-localized dimerization of secretory mucins likely proceeds by similar mechanisms, which is an essential step in the formation of the human gastrointestinal mucus-gels.
authors.affiliation: Pediatric Gastroenterology and Nutrition, Academic Medical Center, Rm 68-260, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: B J
authors.initials: BJ
authors.lastname: van Klinken
authors.forename: A W
authors.initials: AW
authors.lastname: Einerhand
authors.forename: H A
authors.initials: HA
authors.lastname: Büller
authors.forename: J
authors.initials: J
authors.lastname: Dekker
mesh_terms: D002460:Cell Line; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D019281:Dimerization; D018870:Endoplasmic Reticulum, Rough / Q000737:chemistry; D005752:Gastric Mucins / Q000737:chemistry / Q000235:genetics; D005753:Gastric Mucosa / Q000737:chemistry; D006031:Glycosylation; D006801:Humans; D007413:Intestinal Mucosa / Q000737:chemistry; D055271:Mucin 5AC; D055262:Mucin-2; D055257:Mucin-5B; D055272:Mucin-6; D009077:Mucins / Q000737:chemistry* / Q000235:genetics*; D005810:Multigene Family; D011487:Protein Conformation; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics
chemical_list: D005752:Gastric Mucins; C524625:MUC2 protein, human; C524678:MUC5AC protein, human; C524578:MUC5B protein, human; C524734:MUC6 protein, human; D055271:Mucin 5AC; D055262:Mucin-2; D055257:Mucin-5B; D055272:Mucin-6; D009077:Mucins; D011498:Protein Precursors